Periodic Reporting for period 1 - pHioniC (pH and Ion Transport in Pancreatic Cancer)
Reporting period: 2018-11-01 to 2020-10-31
The program’s central hypothesis has a strong grounding in the organ physiology of the exocrine pancreas. Secretion of the alkaline pancreatic juice, normally associated with digestion, produces intermittent acidifications of the pancreas stroma resulting in an acid adaptation of pancreatic cells. We are first to propose that this adaptation facilitates PDAC initiation and progression by selecting for more aggressive phenotypes in interplay with PDAC driver mutations. An acidic microenvironment drives cancer progression by selecting aggressive cellular phenotypes e.g. with higher metastatic potential, but the underlying mechanisms are not clear. Early PDAC stages can be dormant for decades and some may not develop into full-blown disease. At this stage, acid selection of specific cancer phenotypes may trigger disease progression. A better understanding of the underlying pH-dependent mechanisms is required for designing innovative therapeutic concepts.
Our research therefore aims to achieve the following main goals:
(i) to map the pancreatic pH landscape and determine how it influences the onset and progression of disease in in vitro organoids and in animal models of PDAC in vivo;
(ii) to dissect, using tractable cell/organoid models in vitro, the mechanisms by which pH influences the disease, and how the tumour shapes its pH landscape;
(iii) to develop methods for modifying or exploiting pancreatic pH in a bid to influence the disease trajectory in the experimental and preclinical setting.
ad (i): Several new in vitro cell models and organoid preparations have been developed and new ex vivo preparations are currently optimized. Their common denominator is to mimic the characteristic properties of the PDAC microenvironment as closely as possible. This includes (the combination of) aciditiy, hypoxia, matrix composition and their mechanics as well as coculturing of tumor and stroma cells.
ad (ii): We identified a number of new ion channels whose expression and/or activities have previously not been studied in PDAC tumor and/or stroma cells. Moreover, we started to assess their pH sensitivity and how this modifies their ability to regulate the aggressive cancer cell behavior such as cell proliferation, apoptosis or cell migration.
ad (iii): We started to explore the extracellular pancreatic pH landscape in in vitro and ex vivo preparations. Moreover, we have developed ADCs targeting a pH regulatory protein and an ion channel strongly expressed in the acidic and hypoxic PDAC microenvironment.